Transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, acneiform eruptions, acne vulgaris, and seborrheic dermatitis are common dermatological diseases. Each has its own etiology and histology.
1. Transient Acantholytic Dermatosis
Transient acantholytic dermatosis, also called syn Grover's disease, is an acquired skin disease which is seen as itchy papules and vesicles resulting in soreness over the area. The lesions appear on the shoulders, neck, thighs, scalp rapidly. Some of the papules can become rough and may have crusting. The disease mostly occurs in meddle to old age, especially in men. Unlike the name of the disease, the condition is not transient, and can last for years.
The cause of the disease is unknown, however, various factors are thought to precipitate the disease, including sun exposure and sun burn, heat exposure, sweating, fever, radiation treatment, and cancers. There is no specific treatment for this disease. Currently, topical steroids, systemic steroids, oral vitamin A, etretinate, PUVA (psoralen and long-wave ultraviolet radiation) and Accutane® (isotretinoin, manufactured by Roche) have been used clinically.
2. Acne Miliaris Necrotica and Acne Varioliformis
Acne miliaris necrotica, also called scalp folliculitis, consists of follicular vesicopustules, frequently solitary, usually very itchy and tender, which appear anywhere in the scalp or adjacent areas. It can range from an occasional nuisance that many people experience to a chronic problem that can be quite troublesome. The severe form of the disease which leaves large scars is called acne varioliformis. The condition is more common in people who are doing activities that make them sweat or who wear occlusive head gear. Stress often seems to trigger outbreaks as well. Existing treatments range from antibiotic shampoos such as Capitrol® (a chloroxine shampoo), astringent compresses, topical antibiotics or steroids to oral antibiotics. In extreme cases, Accutanee has been used, which is well known for the severe adverse side effects that can cause.
3. Perioral Dermatitis
Perioral dermatitis is a chronic papulopustular facial dermatitis. It mostly occurs in younger women. The incidence is estimated as 0.5-1% in industrialized countries, independent of geographical factors. The disease is limited to the skin. Skin lesions occur as grouped follicular reddish papules, papulovesicles and papulopustules on erythematous base with a possible confluent aspect. In an extreme variant of the disease, called lupuslike perioral dermatitis, granulomatous infiltrates occur with a yellowish aspect in diascopy. Although perioral dermatitis is limited to the skin and not life threatening, emotional problems may occur due to the disfiguring character of the facial lesions and a possible prolonged course of the disease.
The etiology of perioral dermatitis is unknown. However, many causative factors have been suggested, including injudicious use of topical steroids, fluorinated toothpaste, skin care ointments and creams, especially with a petrolatum or paraffin base and the vehicle isopropyl myristate, and old or contaminated make-up or applicators. It is known that UV light, heat and wind worsen perioral dermatitis. Further, microbials such as fusiform spirilla bacteria, candida species and other fungi have been found from the lesions. Other microbiological factors, such as candidiasis have been reported to provoke perioral dermatitis. In addition, hormonal factors, and gastrointestinal disturbances have been considered as well.
Known treatments include oral tetracyclines, minocin and doxycycline, with discontinuing topical corticosteroids, and avoiding lauryl sulfate toothpaste. However, it is currently believed there is no medicine that one can apply directly to the skin which will help perioral dermatitis.
4. Acneiform Eruptions
Acneiform eruptions are characterized by papules and pustules resembling acne lesions, not necessarily confined to the usual sites of acne vulgaris. The eruptions are distinguished by their sudden onset, usually in a patient well past adolescence. Most of the acneiform eruptions originate from skin exposure to various industrial chemicals. Some eruptions may come from oral medications. Acneiform eruptions may be induced by exposure of the skin to the fumes generated in the manufacture of chlorine and its by-products. Cutting oils, lubricating oils, crude coal tar applied to the skin for medicinal purposes, have tar distillates, coal tar pitch, and corticosteroids applied to the skin under occlusive dressings, and asbestos are known substances that may produce acneiform eruptions. Some of the acneiform eruptions are induced by medications such as iodides in vitamins with mineral supplement, and bromides in drugs such as propantheline bromide, and corticosteroids.
Although commonly called “trade acne”, “bromine acne”, and “chloracne”, acneiform eruptions are not a true acne, even though they are often ushered in by open comedones. Current treatments of acneiform eruptions include massive keratinization-suppressing doses of vitamin A, 300,000 units daily, topical retinoids, such as Retin-A cream or gel, or even oral Accutane®.
The above-discussed dermatoses are commonly seen clinically. Some patients respond well to the existing treatments. However, many patients suffer from the diseases for many years without significant improvement after being treated with all existing treatments. Furthermore, some patients have adverse reactions to the existing medications, or can not tolerate antibiotics used for treating these dermatoses. Sometimes, it is not appropriate to use existing treatment methods or medications for certain patients. For example, antibiotics and Accutane® are effective for treating acute inflammation caused by these dermatoses, however, they should not be used for pregnant women and nursing mothers. Therefore, there is apparently a need for new and effective topical treatments for the above-mentioned dermatoses.
5. Acne Vulgaris
Acne vulgaris, known as acne by the general public, is a common and multifaceted skin disorder of the hair follicles and sebaceous glands. Although it affects almost 100% of adolescents to varying degrees and generally wanes as adolescence ends, the disease may persist into adulthood. Adult women, in particular, may be affected and may experience premenstrual flares. However, severe acne vulgaris tends to be more common in adolescent males than in people of other age-groups.
At least four factors contribute to the development of acne: follicular plugging, increased sebum production by the sebaceous glands, colonization of the sebaceous follicles with Propionibacterium acnes, and inflammation. Propionibacterium acnes is the most common gram-positive, non-spore forming bacteria, a common resident of the pilosebaceous glands of the human skin. It is the causative agent of acne vulgaris.
Follicular plugging occurs when desquamating cells lining the follicular lumen stick together, rather than flowing to the surface with sebum. This occurs because of abnormal keratinization, components of which are increased cell division and increased cohesiveness of cells lining the follicular lumen. These cells mix with sebum, plug the opening of the hair follicle, and form a closed comedo (commonly called whitehead). If this mixture protrudes from the follicular opening, it turns a dark color (blackheads).
During adolescence, when sebum production increases, the sebaceous follicles become colonized with Propionibacterium acnes. This anaerobic diphtheroid hydrolyzes sebum into free fatty acids, which serve as the primary proinflammatory substances of acne vulgaris. Propionibacterium acnes also secrete chemotactic factors that attract neutrophils. Lysosomal enzyme released from the neutrophils rupture the follicle wall releasing proinflammatory mediators including keratin and lipids into the surrounding dermis. The resulting inflammation forms erythematous papules or pustules, nodules, cysts, or abscesses. If the inflammation is severe, as in cystic acne, the skin may eventually scar.
Therefore, the key features of the pathogenesis of acne vulgaris can be characterized as 1) increased sebum production, 2) hyperkeratinization of the neck of the follicles, 3) bacterial proliferation, and 4) inflammation. Acne vulgaris can be classified into three categories: comedonal, inflammatory, and nodulocystic. Within each category, acne vulgaris can be further divided into mild, moderate, or severe, based on the number of lesions and the amount of skin involved.
Effective management of acne vulgaris can be accomplished by addressing the four key features of the pathogenesis. Topical therapy is usually the first choice for patients with mild-to-moderate inflammatory acne. The use of topical therapy minimizes potential side effects associated with the use of systemic agents. Topical therapies include benzoyl peroxide, which is the most commonly used non-prescription acne medication. It is an important antibacterial oxidizing agent that can decrease the number of Propionibacterium acnes and frequently the amount of free fatty acids. Benzoyl peroxide is the first line monotherapy for mild acne vulgaris and it is available in over-the-counter preparations. Benzoyl peroxide is applied once or twice daily and patients often experience mild redness and scaling of the skin during the first week of usage.
Tretinoin is the most effective topical comedolytic agent currently, decreasing the cohesiveness of follicular epithelial cells, and thereby inhibiting the formation of microcomedones and increasing cell turnover resulting in expulsion of existing comedones. This agent also decreases the thickness of the stratum corneum and potentiates the penetration of topical antibiotic agents. Tretinoin therapy comprises once daily application. Mild redness and peeling are a part of the therapeutic effect of the medication but can result in reduced patient compliance. The improvement may take as long as 6 to 12 weeks, and flare-ups of acne vulgaris can occur during the first few weeks of therapy.
Mild inflammatory acne vulgaris lesions can also be treated with topical antibiotics including erythromycin ointment, clindamycin solution, and meclocylcine cream. The primary action of the antibiotics is to reduce the population of Propionibacterium acnes in the sebaceous follicle and thereby suppress the free fatty acid production. The effectiveness of topical antibiotics in the treatment of acne is limited by their low lipid solubility and subsequent difficulty in penetrating sebum-filled follicles. Topical antibiotics are applied twice daily.
Patients with moderate to severe inflammatory acne often require oral antibiotics in addition to topical therapy. The most commonly prescribed agents include tetracycline, erythromycin, minocycline, and doxycycline. Treatment is usually maintained for several months. Side effects include the overgrowth of nonsusceptible organisms, including Candida, which can produce vaginal and oral yeast infections.
Patients with severe inflammatory acne vulgaris unresponsive to other therapy may require treatment with oral isotretinoin. Isotretinoin is a compound related to vitamin A, and is the only agent that decreases sebum production and reverses the abnormal epithelial formation process. This agent can also decrease number of Propionibacternum acnes in the sebaceous follicle. Duration of therapy is usually 20 weeks, and the satisfactory response rate is quite high. However, treatment is often accompanied by many side effects, including dry skin, pruritus, epistaxis, and photosensitivity, as well as hypertriglyceridemia, abnormal liver function tests, electrolyte imbalances, and elevated platelet counts. Most serious though, is the teratogeric effect of isotretinoin. Use of isotretinoin during pregnancy is absolutely contraindicated. So serious is the potential for death or teratogenic effects to a fetus, isotretinoin is practically contraindicated in women of child-bearing age. Use of isotretinoin must be accompanied by a guarantee by the patient that conception will be avoided at any and all costs.
Because acne vulgaris is a multifactorial disease which is manifest to varying degrees, it is important for the physician to assess the patient to attempt to find therapies which will be helpful to the patient without causing major side effects. All of the current conventional treatments are associated with some degree of adverse side effects that limit their usefulness.
6. Seborrheic Dermatitis
Seborrheic dermatitis, also known as seborrheic eczema and seborrhea, is a chronic superficial inflammatory disease of the skin capable of affecting many parts of the body including the scalp, eyebrows, nasolabial creases, lips, ears, sternal area, axillae, submammary folds, umbilicus, groins, and gluteul crease. The disease is characterized by many shapes, sizes, and surface textures and is often crust-like, yellowish, and accompanied by itching. This is also characterized by remission and exacerbation.
The etiology, pathogenesis and histology of seborrheic dermatitis is unresolved. However, it bears close clinical resemblance to psoriasis and many researchers are of the belief that both conditions share a related etiology, notwithstanding that psoriasis is a broader and less definable condition. Therein, psoriasis typically differentiates over seborrheic dermatitis in its absence of itching and its resistance treatment by compounds, such as, selenium sulfide and zinc pyrithione which have been employed in the treatment of seborrheic conditions.
The preferred compound that is used to illustrate the present invention is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B1a and less than 20% 22,23-dihydroavermectin B1b. The following molecular structure represents the avermectin series of compounds, which can be chemically converted to useful derivatives as discussed below.
wherein R is the 4′-(alpha-L-oleandrosyl)-alpha-L-oleandrose group of the structure:
wherein the broken line indicates a single or double bond; R1 is hydroxy and is present only when said broken line indicates a double bond; R2 is isopropyl or sec-butyl; and R3 is methoxy or hydroxy.
The avermectins, of which ivermectin, a chemically produced analog, is a member, are a series of compounds isolated from the fermentation broth of a C-076 producing strain of Streptomyces avermitillis and also chemically produced derivatives thereof. There are eight different but closely related compounds are produced by S. avermitillis, designated as A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b. The production of these compounds is described in U.S. Pat. No. 4,310,519. The preparation of ivermectin is disclosed in U.S. Pat. No. 4,199,569. The disclosures of each of the foregoing patents are incorporated herein by reference. The avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals and also to have agricultural uses against various nematode and insect parasites found in and on crops and in soil.
Some of the avermectins contain a 22,23-double bond. This may be selectively reduced to prepare the ivermectin compounds. In addition, the avermectins possess a disaccharide moiety at the 13-position consisting of the alpha-L-oleandrosyl-alpha-L-oleandrosyl group. One or both of these saccharide groups may be removed as described in U.S. Pat. No. 4,206,205, and the produced aglycone derivatives have a hydroxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571; the latter patent also describes the 13-halo derivatives. The avermectin compounds and derivatives have several hydroxy groups which may be acylated as described in U.S. Pat. No. 4,201,861. U.S. Pat. No. 5,055,454 describes invert position 13 of avermectin from a normal alpha stereochemistry to the epimeric 13-beta stereochemistry. U.S. Pat. No. 5,077,308 describes avermectin aglycone derivatives which incorporate a ketal at position 13. U.S. Pat. No. 5,162,363 describes avermectin derivatives where te 23-position ring carbon atom is replaced with by sulfur atom. U.S. Pat. No. 5,229,416 describes avermectin aglycone derivatives which incorporate two fluorine atoms at position 13 and 23. U.S. Pat. No. 5,262,400 describes avermectin compounds that have various substituents at the 4a-position including alkyl, alkoxy alkyl, or polyalkoxy alkyl groups. Other derivatives of avermectin and ivermectin are disclosed in U.S. Pat. Nos. 4,333,925, 4,963,667, 5,114,930, 5,350,742, and 5,830,875. All the aforementioned patents are incorporated herein by reference. The compounds disclosed in the patents mentioned above share the property of antiparasitic activity with ivermectin.
All avermectin compounds mentioned and referred to above share the spectrum of anti-parasitic biological activity of ivermectin, varying only in degree. It is expected that they will share the activity spectrum of ivermectin needed for them being suitable to use for the purpose of the present invention.
Ivermectin has been used as an antiparasitic agent to treat various animal parasites and parasitic diseases since mid-1980's. It is commercially available for animal use as Cardomec (for felines), Eqvalan (for equines) and Ivomec (for bovines) by Merial, a company of Merck Sharp & Dohme and Aventis. The medicine is available in tablets and chewables for heartworm prevention, topical solution for ear mite treatment, or as oral or injectable solution for other parasite problems.
Ivermectin is also commercially available from Merck & Co., Inc for human use as Stromectol® for eradication of threadworm Strongyloides stercoralis, and for eradication of Onchocerca volvulus. Stromectol® was approved by the U.S. Food and Drug Administration to treat nondisseminated intestinal threadworm (strongyloidiasis) in March 1997. Stromectol® has also been cleared by the U.S. Food and Drug Administration to treat onchocerciasis, or river blindness. The medicine is available in tablets and is orally administered by the patients. The recommended dose of Stromectol® for the treatment of intestinal strongyloidiasis is a single oral dose, two 6 mg tablets for average weight adults (200 micrograms per kilogram of body weight). Stromectol® can also be used in children who weigh 15 kg (33 lb.) or more, at a dose ranging from ½ to 2 tablets.
Magda et al. Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653 describe a method of topical application of ivermectin to treat head lice. Ivermectin is found to have an absolute curative effect after a single topical application.
U.S. Pat. No. 5,952,372 (to McDaniel) discloses a method of treating a form of rosacea associated with the ectoparasite Demodex by orally administering or topically applying ivermectin to fill and eliminate Demodex Follicuorum mites from hair follicles in affected skin. Such treatment results in cessation of the manifestations of allergic and vasomotor responses to the organism that cause the symptoms and signs of rosacea.
U.S. Pat. No. 6,133,310 (to Parks) discloses a method of treating acne rosacea by topically applying ivermectin to the affected areas. Acne rosacea is a different dermatological disease, in term of etiology, and/or histology, from transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions addressed in the present invention. Differential diagnosis is important for the patients to obtain an appropriate treatment and effective prevention of their conditions.